The Use of Deferiprone to Improve Subarachnoid Hemorrhage Cognitive Outcome: U-DISCO

使用去铁酮改善蛛网膜下腔出血的认知结果：U-DISCO

• 批准号: 10222566
• 负责人: David M. Hasan
• 金额: $ 72.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222566
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amygdaloid structure; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Animals; Apolipoprotein E; Atrophic; Attenuated; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Cells; Cerebral hemisphere hemorrhage; Chelating Agents; Clinical Research; Cognitive; Cognitive deficits; Cohort Studies; Confidence Intervals; Control Groups; Cytolysis; Data; Databases; Dementia; Development; Diffuse; Disease Progression; Double-Blind Method; Drainage procedure; Enrollment; Erythrocytes; Exposure to; Family; Ferritin; General Population; Grant; Hippocampus (Brain); Hospitals; Human; Impaired cognition; In Vitro; Intervention; Intraventricular; Ischemic Stroke; Lead; Lipids; Magnetic Resonance Imaging; Measures; Medical; Memory impairment; Neurologic Deficit; Neurons; Outcome; Pathway interactions; Phase; Placebos; Process; Protocols documentation; Randomized; Reporter; Risk; Standardization; Stroke; Structure; Subarachnoid Hemorrhage; Subarachnoid Space; Survivors; Testing; Therapeutic Agents; Therapeutic Effect; Translating; Work; age group; animal data; base; cognitive change; cognitive function; cognitive performance; cognitive testing; cohort; genetic risk factor; hazard; high risk; human model; imaging study; improved; intraventricular hemorrhage; mild cognitive impairment; mortality; mouse model; neuroimaging; neuron loss; population based; post stroke; preclinical study; recruit; risk variant; sex; standard of care; stroke survivor; years of life lost

Project Summary: Aneurysmal subarachnoid hemorrhage (aSAH) has a high mortality rate (~60%), with a large proportion of the survivors becoming functionally dependent. aSAH survivors have long term cognitive deficits and memory impairment in their productive years with major responsibilities with respect to work and family. In a 30-year nationwide population-based cohort study using data from Danish medical databases, the authors computed the absolute risks and hazard ratios (HR) of dementia up to 30 years after stroke. Compared with the general population, the HR (95% confidence interval) for dementia among ischemic stroke survivors was 1.72 (1.66–1.77), 2.70 (2.53–2.89) after intracerebral hemorrhage, and 2.74 (2.45–3.06) after aSAH. Why is that?? In aSAH subjects, accumulation of hemoglobulin (Hb) and non-heme iron (Fe) which are the natural byproduct lysis of red blood cells leads to significant neuronal cells death. Several preclinical studies in animals showed that both products lead to neuronal death and atrophy of any brain structures exposed to it and specifically the hippocampus and amygdala. These data were replicated in human, where authors found, the level of ferritin (Ft) in CSF, a reporter of the amount of Fe in brain, was found to strongly correlate with progression to Alzheimer's disease (AD). What is the mechanistic pathway of this process?? Our group showed that Hb is toxic to neuronal cells in vitro and adding deferiprone (De) attenuated and reversed this effect significantly. We then confirmed these results in a mouse model of intraventricular hemorrhage. Additionally, in a proof-of-concept study we showed that De significantly decreased Ft in CSF (p<0.0001) suggesting a potential therapeutic effect. Furthermore, others also showed in preclinical studies using different animal models, Fe chelating agents decrease Fe content both in the subarachnoid space and intraventricular improving the functional and cognitive outcome in these animals. Therefore, we propose this grant to test the hypothesis that deferiprone, a lipid soluble Fe chelating agent and therefore diffuse easily across the blood-brain barrier, will significantly decrease Ft (a reporter of total non-heme Fe content in CSF) in subjects with aSAH and hence improve cognitive function. To test this hypothesis, we propose a phase 1/2a single-center randomized double-blinded placebo vs. De trial that recruits and enrolls 66 subjects with aSAH who require placement of EVD as a standard of care. Subjects will be randomized equally into 2 groups: A) placebo & B) 15 mg/kg bid for 21 days. Ft will be collected daily from CSF. We will also test the cognitive changes using the Montreal Cognitive Assessment test along with a battery of well-standardized and widely used cognitive tests that measure various aspects of cognitive and behavioral functioning. We will also assess the volume of hippocampus and amygdala in this cohort and compare them to a matched, historic control cohort using specific MRI protocol. These tests will be correlated with the Ft content in CSF and the volume of hippocampus and amygdala on imaging studies obtained.

项目摘要： 动脉瘤性蛛网膜下腔出血（aSAH）的死亡率很高（约60%），其中大部分患者是动脉瘤性蛛网膜下腔出血（aSAH）。 幸存者变得功能依赖。aSAH幸存者有长期的认知缺陷和记忆 在工作和家庭方面承担主要责任的生产年龄受到损害。 在一项基于丹麦医学数据库的30年全国人群队列研究中，作者 计算了中风后30年内痴呆的绝对风险和风险比（HR）。较 在一般人群中，缺血性卒中幸存者中痴呆的HR（95%置信区间）为 1.72（1.66-1.77），脑出血后2.70（2.53-2.89），aSAH后2.74（2.45-3.06）。 “那又怎么样？在aSAH受试者中，血红蛋白（Hb）和非血红素铁（Fe）的积累是ASAH的主要原因。 红细胞的天然副产物裂解导致显著的神经元细胞死亡。几项临床前研究， 动物实验表明，这两种产品都会导致神经元死亡和任何暴露于其下的大脑结构萎缩。 尤其是海马体和杏仁核这些数据在人体中得到了复制，作者发现， CSF中的铁蛋白（Ft）水平是脑中铁含量的报告者， 阿尔茨海默病（AD）的进展。 这一过程的机械途径是什么？我们的研究小组表明，血红蛋白对神经元细胞有毒性， 而加入去铁酮（De）可明显减弱和逆转这种作用。然后我们确认了这些 导致脑室内出血的小鼠模型。此外，在一项概念验证研究中， De显著降低CSF中的Ft（p<0.0001），表明潜在的治疗效果。此外，委员会认为， 其他人也在使用不同动物模型的临床前研究中显示，铁螯合剂降低铁 在蛛网膜下腔和脑室内的含量改善功能和认知结果， 这些动物。因此，我们提出这项补助金，以检验假设，去铁酮，脂溶性铁 螯合剂，因此很容易扩散穿过血脑屏障，将显着降低Ft（a CSF中非血红素铁总含量的报告者），从而改善aSAH患者的认知功能。 为了检验这一假设，我们提出了一项1/2a期单中心随机双盲安慰剂与De试验 招募并入组了66例aSAH受试者，这些受试者需要将EVD作为标准治疗。科目 将被平均随机分为2组：A）安慰剂和B）15 mg/kg bid，持续21天。每日采集FT CSF的。我们还将使用蒙特利尔认知评估测试沿着测试认知变化， 一组标准化和广泛使用的认知测试，测量认知和 行为功能我们还将评估该队列中海马体和杏仁核的体积， 使用特定的MRI方案将其与匹配的历史对照队列进行比较。这些测试将与 并测定脑脊液中Ft含量及海马、杏仁核体积。